Miguel Santos

Mechanically Robust Plasma-Activated Interfaces Optimized for Vascular Stent Applications

The long-term performance of many medical implants is limited by the use of inherently incompatible and bioinert materials. Metallic alloys, ceramics, and polymers commonly used in cardiovascular devices encourage clot formation and fail to promote the appropriate molecular signaling required for complete implant integration. Surface coating strategies have been proposed for these materials, but coronary stents are particularly problematic as the large surface deformations they experience in deployment require a mechanically robust coating interface. Here, we demonstrate a single-step ion-assisted plasma deposition process to tailor plasma-activated interfaces to meet current clinical demands for vascular implants. Using a process control-feedback strategy which predicts crucial coating growth mechanisms by adopting a suitable macroscopic plasma description in combination with noninvasive plasma diagnostics, we describe the optimal conditions to generate highly reproducible, industry-scalable stent coatings. These interfaces are mechanically robust, resisting delamination even upon plastic deformation of the underlying material, and were developed in consideration of the need for hemocompatibility and the capacity for biomolecule immobilization. Our optimized coating conditions combine the best mechanical properties with strong covalent attachment capacity and excellent blood compatibility in initial testing with plasma and whole blood, demonstrating the potential for improved vascular stent coatings.

Immobilization of bioactive plasmin reduces the thrombogenicity of metal surfaces.

Components of many vascular prostheses including endovascular stents, heart valves and ventricular assist devices are made using metal alloys. In these blood contacting applications, metallic devices promote blood clotting, which is managed clinically by profound platelet suppression and/or anticoagulation. Here it is proposed that the localized immobilization of bioactive plasmin, a critical mediator of blood clot stability, may attenuate metallic prosthesis-induced thrombus formation. Previously described approaches to covalently immobilize biomolecules on implantable materials have relied on complex chemical linker chemistry, increasing the possibility of toxic side effects and reducing bioactivity. We utilize a plasma deposited thin film platform to covalently immobilize biologically active plasmin on stainless steel substrates, including stents. A range of in vitro whole blood assays demonstrate striking reductions in thrombus formation. This approach has profound potential to improve the efficacy of a wide range of metallic vascular implants.

Simple one-step covalent immobilization of bioactive agents without use of chemicals on plasma-activated low thrombogenic stent coatings

Abstract This chapter describes a simple measure to address issues in the use of stents, that is, the inherent thrombogenicity of metallic implants, destruction of the protective endothelial cell layer lining arterial walls, chronic inflammation, and the renarrowing of the treated artery (restenosis). Unfortunately, the drugs (taxus and limus family) eluted from drug-eluting stents (DES) to halt restenosis cause endothelial dysfunction and hypersensitivity, contributing to thrombogenic potential. The deposition of biofunctional thin-film coatings, suitable for coronary stents, has been previously demonstrated using plasma-activated coatings (PAC) on various substrates. PAC was designed to overcome many of the thrombogenic properties of metal and DES drugs. Modified tropoelastin, fibronectin, plasmin, and streptokinase, all bound to the stent surface by PAC, have showed promise, as tropoelastin is the major regulator of smooth muscle cell proliferation in vivo, fibronectin encourages endothelial cell regeneration, and plasmin and streptokinase have thrombolytic properties.

Plasma activated coating immobilizes apolipoprotein A-I to stainless steel surfaces in its bioactive form and enhances biocompatibility

We utilized a plasma activated coating (PAC) to covalently bind the active component of high density lipoproteins (HDL), apolipoprotein (apo) A-I, to stainless steel (SS) surfaces. ApoA-I suppresses restenosis and thrombosis and may therefore improve SS stent biocompatibility. PAC-coated SS significantly increased the covalent attachment of apoA-I, compared to SS alone. In static and dynamic flow thrombosis assays, PAC+apoA-I inhibited thrombosis and reduced platelet activation marker p-selectin. PAC+apoA-I reduced smooth muscle cell attachment and proliferation, and augmented EC attachment to PAC. We then coated PAC onto murine SS stents and found it did not peel or delaminate following crimping/expansion. ApoA-I was immobilized onto PAC-SS stents and was retained as a monolayer when exposed to pulsatile flow in vivo in a murine stent model. In conclusion, ApoA-I immobilized on PAC withstands pulsatile flow in vivo and retains its bioactivity, exhibiting anti-thrombotic and anti-restenotic properties, demonstrating the potential to improve stent biocompatibility.

Rapid Endothelialization of Off-the-Shelf Small Diameter Silk Vascular Grafts

Visual Abstract Electrospinning of silk to create nanofibers, which deposit onto a rotating collector. This results in the formation of a pure silk conduit of 1.5 mm internal diameter. These conduits are then implanted into the descending abdominal aorta of Sprague Dawley Rats with end-to-end suturing, and left for 3, 6, 12, and 24 weeks. Endpoint histologic analysis of the explanted grafts demonstrate hyperplasia stabilization, complete endothelialization and excellent blood compatibility.